Testosterone concentrations decline by 1-2% annually as men age, and free testosterone concentrations decline even more rapidly (3-4% per year). Lower serum testosterone concentrations have been associated with important health consequences, including reduced bone mineral density, increased risk of hip fracture, loss of muscle mass, decreased libido and fertility, and increased cardiovascular disease. HYPOTHESIS I will test whether glucocorticoids mediate down- regulation of urea transporter proteins by altering transcription. Specific Aim 1 will test whether glucocorticoids down-regulate UT-A and/or UT-B protein or mRNA expression. Specific Aim 2 will determine the element mediating glucocorticoid-induced suppression of urea transporter promoter activity. HYPOTHESIS II will test whether chronic lithium administration down-regulates urea transporter protein(s) by increasing glucocorticoids. Specific Aim 3 will test whether adrenalectomy prevents long-term down-regulation of urea transporter protein(s) in lithium-treated rats. Specific Aim 4 will test whether elevated lithium levels perturb urea transporter phosphorylation or function in rat inner medulla or in EcR-293 cells that have been stably transfected with a specific urea transporter isoform. HYPOTHESIS III will test whether urea transporter proteins are down- regulated during aldosterone-escape. Specific Aim 5 will test whether mineralocorticoids down-regulate UT-A and/or UT-B protein or mRNA expression.